Cystinuria is a type of kidney stone disease characterized by recurrent formation of cystine-based stones. This painful condition is caused by mutations in the SLC3A1 and/or SLC7A9 gene(s), which code for the two components of the low-affinity high-capacity cystine transporter that is responsible for the reabsorption of cystine and other dibasic amino acids from the urine (Fernandez et al. (2002) Am. J. Physiol. Renal. Physiol. 283(3): F540-F5488; Wang et al. (2009) Comp. Biochem. Physiol. B Biochem. Mol. Biol. 154(1): 157-164; Calonge et al. (1994) Nat. Genet. 6(4): 420-425). Cystinuria patients accumulate low-soluble cystine in their urine, which then precipitate into crystals and aggregate to form painful kidney stones (Dent et al. (1965) Br. Med. J. 1(5432): 403-408; Dent and Senior (1955) Br. J. Urol. 27(4): 317-32). Cystinuria is notable because patients often generate multiple urinary stones at a high frequency of recurrence, often requiring repetitive surgical interventions to remove large stones (Mattoo and Goldfarb (2008) Semin. Nephrol. 28(2): 181-191).
Approximately 7% of American women and 11% of men will experience at least one kidney stone over the course of their lifetime. Kidney stones are an increasing public health problem as the prevalence of kidney stones is increasing worldwide. They are leading cause of mortality in the developing world, and medical expenditures related to stones are estimated to cause $2 billion dollars per year in the United States (Coe et al. (2005) J. Clin. Invest. 115(10): 2598-2608; Scales et al. (2012) Eur. Urol. 62(1): 160-165; Romero et al. (2010) Rev. Urol. 12(2-3): e86-e96). Cystinuria is an autosomal form of kidney stone disorder that affects approximately 1 out of 7,000 people} and represent approximately 1-2% of kidney stone patients and 6-7% of pediatric calculi (Palacin et al. (2001) Curr. Opin. Genet. Dev. 11(3): 328-335).
Much progress has been made in the development of surgical treatments aimed at removing stones from patients afflicted with kidney stones (Sumorok and Goldfarb (2013) Curr. Opin. Nephrol. Hypertens. 22(4): 427-431). However, there have been few advances in the understanding of the stone aggregation process and on the development of non-surgical measures that prevent recurrent stones. Our incomplete understanding of the processes that underlie urinary stone development leaves us with little paths towards the prevention of kidney stones, an important problem as 50% of kidney stone patients, and nearly all cystinuria patients, will incur repeat stone events (Chillaron et al. (2010) Nat. Rev. Nephrol. 6(7): 424-434).
Although the pathophysiology and genetics of cystinuria are well characterized, there has been little progress in {the development of effective interventions aimed at preventing stone recurrence. Hyperhydration (consummation of adequate fluids to result in urinary volumes greater than 3-4 liters per day) and urine alkalization (typically with potassium citrate at 6-8 tablets per day), along with a low animal protein diet, are often recommended to help to suppress cystine precipitation (Dent et al. (1965) Br. Med. J. 1(5432): 403-408). However, nearly all cystinuric patients require pharmaceutical interventions. Commonly prescribed medications include D-penicillamine and tiopronin (Thiola), which compete with cysteine to form the more soluble asymmetric dimers in the urine (Saravakos et al. (2014) Urology, 83(4): 693-699).
Yet in spite of these interventions, cystinuric patients require between 0.14-0.32 procedures per year to remove obstructive cystine stones (Ng and Streem (1999) J. Endourol. 13(9): 647-651; Chow and Streem (1996) J. Urol. 156(5): 1576-1578; Barbey et al. (2000) J. Urol. 163(5): 1419-1423). In addition, D-penicillamine and tiopronin are associated with serious adverse side effects which include nephrotoxicity and other kidney injury in patients whose kidneys are already compromised by recurrent stone formation (Sumorok and Goldfarb (2013) Curr. Opin. Nephrol. Hypertens. 22(4): 427-431; Saravakos et al. (2014) Urology, 83(4): 693-699; ecker (2007) Caring for Australians with Renal Impairment, The CARI guidelines. Kidney stones: cystine stones. Nephrology (Carlton), 12(Suppl 1): S4-S10; Koraishy et al. (2013) Am. J. Kidney Dis. 62(4): 806-809). Many cystinuric patients thus resort to kidney transplants as recourse (Hoitsma et al. (1983) JAMA 250(5): 615; Capelli et al. (2015) Kidney Transplantation and inborn errors of metabolism]. G Ital Nefrol, 32(2)).